The present invention relates to an apparatus for the xe2x80x9cin vivoxe2x80x9d diagnosis by means of a light-induced reaction created by an endogenous or exogenous photo-amboceptor.
In order to trigger a light-induced reaction in biologic systems a photo-amboceptor is administered to the patient in a concentration of a few mg/kg body weight.
Typical photo-amboceptors or sensitisers are Photofrin or Photosan, which present a basic hemato-porphyrin framework structure, protoporphyrin IX induced by xcex4-amino-laevulic acid (ALA) (PPIX), which has been used in urology and dermatology for a short time, 9-Oac-tetramethoxy porphycene, benzoporphyrin derivatives, as-partyl chlorine E6, m-tetrahydroxyphenyl chlorine, Sn(IV) etiopurpurine or Zn(II) phthalocyanine.
These substances accumulate in tumour tissues in a concentration increased by roughly two to fifteen times. This selective concentration in tumour tissue is the decisive basis of the photodynamic diaghosis (PDD) and photodynamic therapy (PDT).
For diagnosis the tissue to be analysed is irradiated after an appropriate waiting period following the administration of the photo-amboceptor, with blue or violet lightxe2x80x94in known devices with laser light almost exclusively. The photo-amboceptor, which is present in an increased concentration in tumour tissue, is excited by this light and displays in response a typical red fluorescence by which the tumour can be localized.
Apart from fluorescencexe2x80x94which is produced by a photo-amboceptor accumulated in the tissuexe2x80x94the so-called autofluorescence of the tissue may be triggered, too, which is brought about by endogenous fluorescent pigments. In this case mostly blue or ultraviolet light is used for excitation as well.
In dependence on the respective photo-amboceptors used, the photodynamic diagnosis (PDD) entails certain problems. When photofrin and photosan-3 are used as photo-amboceptors in photodynamic diagnosis highly complex engineering devices are required for the detection of fluorescence because, on account of interfering autofluorescence fractions, only very complex computer-assisted image processing techniques and highly sensitive cameras with residual-light intensifier are suitable for an appropriate detection of the fluorescence in tumor tissue.
When xcex4-aminolaevulic acid (ALA) is used the induced fluorescence is strong enough for recognition merely by visual inspection.
However, the fluorescence achieved by means of xcex4-aminolaevulic acid does not furnish an optimum quality of the image which is to be recorded as part of the diagnosis. This is due, inter alia, to variabilities of the optical tissue parameters which take an influence on the fluorescent intensity in a non-specific manner.
It is moreover known to use photo-amboceptors for photodynamic therapy (PDT). In this respect reference is made to the document WO 93/20810, which is, by the way, also referred to explicitly with respect to the explanation of all terms and steps of operation which are not described here in more details.
The devices used for photodynamic diagnosisxe2x80x94which is also referred to as fluorescent diagnosisxe2x80x94or for photodynamic therapy, respectively, which are also termed xe2x80x9cPDDxe2x80x9d or xe2x80x9cPDTxe2x80x9d devices, comprise an illuminating system, a light-feeding unit which directs the light from the illuminating unit to the tissue region to be diagnosed and/or treated, and an imaging, an image-recording and possibly an image-transmitting unit which images the light coming from the tissue region into a proximal image plane.
The illuminating system and the light-supplying unit define the path of the illuminating beam whilst the imaging, the image-recording and possibly the image-transmitting unit define the path of the observation beam.
In an endoscopic PDD device the light-supplying unit consists of the light guide, which connects the illuminating system to the light guide connector of the endoscope, for instance, and the illuminating light guide of the endoscope. The light guide may be a quartz light guide or a fluid light guide, for instance. Fluid or quartz light guides offer a better transmission in the blue or violet range than standard glass light guides. The endoscope lens, which is disposed on the distal end and covers the tissue range illuminated by the light emerging from the illuminating light guide, constitutes the image-recording unit; the image of the lens is picked up, for instance, by means of one or several CCD receivers which serve as opto-electronic image converter unit. When the CCD receiver is disposed on the proximal end the lens image is transmitted by a relay lens system or an imaging fiber bundle which hence fulfill the function of the image-transmitting unit.
In the PCT application PCT/DE 96/01831, which is not a prior publication, it has been proposed to perform endoscopic photodynamic diagnosis and therapy by means of an apparatus in which a xe2x80x9csource of white lightxe2x80x9d is used as light source rather than a laser, i.e. a light source which generates incoherent light in the wavelength range of at least from 390 to 650 nm. The light from the light source is fed via a focusing unit into the fiber optic light guide.
The aforementioned application contains moreover the proposal to harmonize the spectral internal transmittance factor or the (spectral) transmission function, respectively, of the light-feeding unit with the spectral internal transmittance factor or the (spectral function), respectively, of the imaging or image-recording unit in such a way that only a fraction of the light reflected on the irradiated tissue contributes to the production of the image, which is so dimensioned that the fluorescent image will not be glared or blanketed by this xe2x80x9cbackground picturexe2x80x9d.
Filter systems are used, as a rule, to set the transmission function. The filter systems so far proposed entail the disadvantage, however, that small errors due to tolerances are sufficient to result in major variations of the reflected light quantity which contributes to the production of the image, which errors occur particularly in terms of the edge position and the steepness of the transmission edge. This effect, in its turn, results in a major change of the ratio between the fluorescent light and the background light.
When, for instance, the filter graph of the filter system introduced into the path of the illuminating beam is shifted towards shorter wavelengths as a result of manufacturing or assembly faultsxe2x80x94tilting of the filter, etc.xe2x80x94the overlapping of the transmission zones of the filter systems introduced into the paths of the illuminating and observation beams is practically reduced to xe2x80x9czeroxe2x80x9d in the event of small shifts already so that a background image is not obtained as a result of the directly reflected light and only a fluorescent image is achieved.
Vice versa, with a small shift towards longer wavelengths already an excessive overlapping is achieved so that the fluorescent image is blanketed by the visible (xe2x80x9cnonxe2x80x9d-fluorescent) background picture.
Moreover, a variation of the steepness of the transmission edge also displaces the position of the transmission graph in the lower transmission range so that this error requires compensation like an edge position error. In the upper range the overall transmission is, as a matter of fact, subjected only to a slight change.
Similar problems occur also in devices where a photodynamic diagnosis is performed by means of a microscope and particularly a surgical microscope. Appropriate devices are described in the European Patent EP 0 241 268 A1 or the U.S. Pat. No. 5,371,624.
The problems which may occur in filter selection are described also in the U.S. Pat. No. 4,056,724xe2x80x94cf. FIG. 14 in particular.
In all other respects explicit reference is made to these prior art documents as far as the explanation of all terms is concerned which are not described here in details.
The present invention is based on the problem of proposing a spectral internal transmittance characteristic or a transmission function for the path of the illuminating beam and/or the path of the observation beam, in which tolerance-induced errors, particularly in terms of the edge position and the steepness of the transmission edges, produce distinctly lower effects than other systems as far as the ratio between the light quantities of the fluorescent light and the directly reflected light is concerned which contributes to the production of the image.
Inventive solutions to this problem are defined in Patent Claim 1. Improvements of the invention are the subject matters of Claims 2 to 9. The Claims 10 and 11 relate to filters for use in a PDD apparatus.
The invention is based on the fundamental idea of designing the transmission graphs in such a way that at least one of the transmission graphs presents a section having a xe2x80x9cflat slopexe2x80x9d so that edge position and edge steepness errors take only a slight influence on the overall transmission. With this provision the effect is achieved that the overall transmission, which is achieved by a convolution of the transmission of the path of the illuminating beam with the transmission of the path of the observation beam and by integration over the relevant wavelength range, will be influenced only slightly by the displacement of the edge position and/or the steepness of the transmission edge.
In accordance with the invention therefore the spectral internal transmittance or the spectral transmission function T1(xcex), respectively, of the light-feeding unit or the path of the illuminating beam is therefore matched with the fluorescence excitation spectrum of the photo-amboceptor or of the tissue, respectively, and the spectral internal transmittance or the spectral transmission function Tb(xcex), respectively, of the imaging unit or of the path of the observation beam, respectively, with the fluorescence spectrum of the photo-amboceptor or the tissue, respectively. Moreover, the transmission function T1(xcex) of the path of the illuminating beam intersects the transmission function Tb(xcex) of the path of the observation beam at a transmission value not exceeding 30%.
The invention starts out from the basic idea that the transmittance levels or the spectral transmission functions, respectively, of the paths of the illuminating and observation beams intersect in a zone where at least one transmittance graph presents a flat slopexe2x80x94at least in the event of averaging or substitution of the actual graph by a straight line over a wavelength range from 10 to 30 nmxe2x80x94so that a displacement of one or of both graphs entails only a comparatively slight variation of the area enclosed by the two graphs.
To this end it is decisive that there is at least one reference wavelength xcexr which is longer by 2xcex94xcexs at maximum or shorter than the wavelength xcexs at the point of intersection, for which hence applies
xcexsxe2x88x922xcex94xcexxe2x89xa6xcexrxe2x89xa6xcexs+2xcex94xcex
and starting out from which the spectral transmission function T1(xcex) of the path of the illuminating beam satisfies the following conditions for at least five wavelengths xcexr, xcexr+xcex94xcex, xcexr+3xcex94xcex, xcexrxe2x88x92xcex94xcex, and xcexrxe2x88x922xcex94xcex:
wherein
xe2x80x834 nm less than xcex94xcex less than 6 nm
and/or the spectral transmission function Tb(xcex) of the path of the observation beam satisfies the following conditions for at least five wavelengths xcexr, xcexrxe2x88x92xcex94xcex, xcexrxe2x88x923xcex94xcex, xcexr+xcex94xcex, and xcexr+2xcex94xcex:
wherein
4 nm less than xcex94xcex less than 6 nm.
The transmission functions in the light-feeding and the image-producing section of the inventive apparatus are so selected that only a precisely set light quantity of the illuminating light, which is reflected on the tissue and has naturally a comparatively high intensity, xe2x80x9carrivesxe2x80x9d through the imaging apparatus section in the proximal image plane whereas light having a wavelength xcex can arrive from the zone where fluorescence occurs in the proximal image plane only if it comes from the illuminated tissue region rather than from the illuminating system.
The inventively selected transmission functions of the path of the illuminating beam and of the path of the observation beam of the apparatus ensure that the illuminated tissue region is so strongly irradiated with light of a wavelength which is not within the range of the fluorescence spectrum, so that the examining person can perceive details of the illuminated tissue region independently of the fluorescent radiation on account of the light directly reflected in this wavelength region, which furnishes a background picture.
In other terms, in accordance with the invention the image of the tissue region illuminated with exciting light is produced simultaneously by means of fluorescent light and reflected illuminating light, with the two fractions, which contribute both to the production of the image, being so set in terms of their wavelength and with respect to their intensity that they will not xe2x80x9cinterferexe2x80x9d with each other.
It is preferable to have the setting made in such a way that the intensity of the emitted fluorescent light is within the same order as the overall intensity of the reflected fraction of the exciting light of the illuminating systemxe2x80x94weighted by the filter characteristic of the observation system. In a particularly expedient form the setting is made such that the two intensities are roughly the same.
It is moreover expedient that the two spectral transmittances intersect at a value less than 10%, preferably at a value less than 5%.
In an improvement of the invention the transmission function of the path of the illuminating beam has an almost horizontal plateau or a local maximum within the range xcexr . . . xcexr+3xcex94xcex and/or the transmission function of the path of the observation beam has an almost horizontal plateau or a local maximum within the range xcexr . . . xcexrxe2x88x923xcex94xcex.
When an ALA-induced PPIX has been selected as photo-amboceptor it is preferable that the spectral transmittance of the path of the illuminating beam satisfies the following relationship
100% greater than T1(xcex)400 . . . 420)xe2x89xa680%
15% greater than T1(xcex)440 . . . 455)xe2x89xa60.5%.
With this configuration of the spectral transmission function of the light-feeding unit and the imaging unit the effect is achieved that the fluorescent light may be clearly perceived with a high contrast on the image of the vicinity of a tumour, for instance, which is produced by the illuminating light.
For an adaptation to the various photo-amboceptors and/or different diagnostic conditions or for a conversion of the inventive apparatus to a therapeutic technique it is moreover preferred that the transmission properties of the light-transmitting and the imaging units can be adjusted by means of one or several optical elements.
The optical elements which are used to set the transmission functions of the light-transmitting and the imaging units are preferably filter systems such as absorption filters, interference filters or even prisms as well as electrically controllable LC filters (liquid crystal filters) which are adapted for being introduced into the paths of the illuminating and observation beams. In this set-up the expression xe2x80x9cpath of the illuminating beamxe2x80x9d is understood to denote the optical path from the lamp of the light source to the light-feeding unit, through this unit and from this unit to the tissue region under diagnosis. The optical elements and particularly the filter systems may be arranged, on principle, at any point of this optical path, preferably at points where the optical path is parallel. However, the arrangement between the illuminating system and the light-feeding unit, i.e. ahead of a light guide fiber bundle, for instance, is particularly preferable. In the description of the filter system or systems the internal transmittance of the respective optical path without filter system is assumed to be 100%.
By way of analogy, the expression xe2x80x9cpath of the observation beamxe2x80x9d is understood to denote the optical path from the illuminated tissue region to the imaging unit and from this unit to proximal image plane. (without a filter system here, too, the internal transmittance is assumed to be 100%.) A fine adjustment of the transmission graphs of the paths of the illuminating or observation beam may be effected by means of supplementary tilting of the filter elements.
When the inventive apparatus is integrated into an endoscope the image plane in the endoscope may be located both in the region of the distal endxe2x80x94e.g. when a video chip is used which is disposed on the distal endxe2x80x94and in the region of the proximal end. In the latter case the path of the observation beam includes, in addition to a lens as image-receiving optical unit, a relay lens system or a flexible fiber bundle, for instance, as image-transmitting unit. When a relay lens system or a fiber bundle is employed as image-transmitting unit the filter systems introduced into the path of the observation beam are preferably disposed between the xe2x80x9clast flatxe2x80x9d of the relay lens system or the exit facet of the fiber bundle, respectively, and the proximal image plane.
When the inventive apparatus is integrated into a surgical microscope the microscope lens system is an element of the imaging unit, which may be followed, for instance, by a video pickup as electronic image-recording unit.
The color filters of the video chip are disregarded in the filter characteristic. Further filters, which are possibly provided in the optical path, must, however, also be considered in the determination of the internal transmittance.
In another embodiment of the invention the filter, which may be introduced into the path of the illuminating beam, includes at least two separate filters whereof one is a thermoresistant interference filter unit whilst the other one is a thermoresistant heat-absorbing filter. The thermoresistant interference filter unit, in its turn, consists preferably of a short-pass and a blocking filter, which are disposed on separate substrates. This leads to distinctly improved transmission properties.
In one exemplary embodiment such a filter for use in the path of the illuminating beam of a PDD device, specifically when ALA-induced PPIX is used as photo-amboceptor, presents a spectral transmission function T1(xcex) which satisfies the following conditions for at least five wavelengths xcexr, xcexr+xcex94xcex, xcexr+3xcex94xcex, xcexrxe2x88x92xcex94xcex, and xcexrxe2x88x922xcex94xcex:
wherein
4 nm less than xcex94xcex less than 6 nm,
with xcexr representing a reference wavelength which is selected as a function of the respectively used photo-amboceptor or the respective autofluorescence, respectively, and for which applies, for instance, when ALA is used as photo-amboceptor:
438 nmxe2x88x922xcex94xcexxe2x89xa6xcexrxe2x89xa6438 nm+2xcex94xcex.
In another exemplary embodiment such a filter for use in the path of the observation beam in a PDD apparatus, particularly when ALA-induced PPIX is used as photo-amboceptor, has a spectral transmission function T1(xcex) which satisfies the following conditions for at least five wavelengths xcexr, xcexrxe2x88x92xcex94xcex, xcexrxe2x88x923xcex94xcex, xcexr+xcex94xcex, and xcexr+2xcex94xcex:
wherein
4 nm less than xcex94xcex less than 6 nm,
with xcexr representing a reference wavelength which is selected as a function of the respectively used photo-amboceptor or the respective autofluorescence, respectively, and for which applies, for instance, when ALA-induced PPIX is used as photo-amboceptor:
438 nmxe2x88x922xcex94xcexxe2x89xa6xcexrxe2x89xa6438 nm+2xcex94xcex.
The filter may be an interference filter in particular, having quartz or a heat-resistant glass such as xe2x80x9cSchoft Borofloatxe2x80x9d as a substrate material.
When another photo-amboceptor is used the filter properties must be appropriately adapted:
The use of optical elements and filters in particular for taking an influence of the transmission characteristic or transmission function, respectively, of the optical path presents the advantage that a normal white-light illumination and observation may be performed, for instance when the filters are tilted out of the path so that the examiner such as a surgeon can assess the tissue region examined by a fluorescence diagnosis, inter alia by the color. The color is an essential criterion of assessment in the field of ophthalmology, for instance.
Common light sources, and specifically light sources known from endoscopy, may be used as light sources, too, which emit wide-band light over the aforementioned wavelength range. Such a light source which emits light with a sufficient intensity is, for example, a gas discharge lamp and a xenon discharge tube in particular. If in an isolated case the luminous efficacy of the light source should be insufficient it is possible to use a xe2x80x9cpulsedxe2x80x9d light source such as a flash device with a flash lamp or even a laser in addition to a xe2x80x9ccontinuously operatingxe2x80x9d light source.